This project is focused on the clinical study of patients with AIDS-related malignancies. Much of the work is focused on tumors associated with Kaposis sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). This virus is the cause of Kaposis sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castlemans disease (MCD). We are also studying antibody to VEGF (bevacizumab) as a therapeutic agent in KS as well as BAY 43-9007 (sorafineb). Bevacizumab was shown in an initial trial to have clinical activity in about 30% of patients. Sorafineb is of interest because it can downregulate several receptors for VEGF. We are also conducting a trial of bevacizumab in combination with liposomal doxorubicin in patients with severe KS. We are conducting a trial of pomalidomide in KS, and preliminary results indicate that it has substantial activity. We ahave also initiated a follow-up trial to study the ciombination of pomalidomide and liposomal doxorubicin in patients with more severe KS. We have initiated a clinical trial to study the natural history of MCD and to explore various treatments. Some of the treatments include the combination of AZT and valganciclovir, a pro-drug of ganciclovir; liposomal doxorubicin and rituxuimab; and toclizumab, a monoclonal antibody against the intrleukin-6 receptor. Results show that AZT plus ganaiclovir has substantial activity, although relapses are common when used alone. In addition, we are studying other patients with KSHV infection to assess factors that may be linked to malignancy. We are exploring methotrexate-based therapy for primary central nervous system lymphoma (PCNSL). We have identified a group of patients with a new KSHV-related syndrome, called KSHV inflammatory cytokine syndrome (KICS), and opened a protocol to study this new disease. As part of this study, we are testing several possible therapies. As part of this effort, we are collaborating with a number of other investigators to conduct translational studies related to HIV, AIDS-malignancies. In collaboration with the Cancer Immunotherapy Trials Network, we are planning a phase I and feasibility trial of the anti-PD-1 inhibitor pembrolizumab in HIV-infected patients with a wide range of malignancies. Finally, we are initiating a trial of lenalidomide, rituximab, and infusional chemotherapy for patients with primary effusion lymphoma.